An unexpected synthesis of ketene monothioacetals.
Some dithiocarbonates (xanthates) can be converted into ketene monothioacetals through extrusion of sulfur upon treatment with base and an alkylating agent.
Acetals↗
Biomedical subjects
Stéphanie Fabre
Publications and source records attributed to Stéphanie Fabre.
[PI3-kinase: Linking immunological synapse to T-cell proliferation].
T cell clonal expansion contributing to host defense against pathogens is a tightly controlled process to maintain the homeostasis of the immune system. Our understanding of how T cell growth and proliferation are controlled following antigenic stimulation is therefore a major challenge. Antigen recognition occurs when a naive T lymphocyte contacts an antigen-presenting cell. A specialized junction enriched in T-cell receptors, costimulation molecules and signaling adaptors, called the immunological synapse, is then created for several hours between the two cell types. Recent discoveries now clarify the molecular mechanisms used by this organization to control T cell growth and proliferation. It has been established that the immunological synapse functions in fact as an integrative platform where class Ia phosphoinositide-3-kinases (PI3Ks) are recruited and activated to continuously produce high levels of 3'-phosphoinositides. These lipids regulate the localization and the activation of a wide range of PH-domain containing proteins, among which the serine-threonine kinase Akt, a downstream effector of PI3Ks, appears to be a key player. FoxO (Forkhead subgroup O) family members control in various cell systems genes implicated in apoptosis, stress resistance and cell cycle arrest, thereby contributing to maintain quiescence in unstimulated cells. In naïve T cells contacting antigen-presenting cells a rapid but also very prolonged nuclear exclusion of these transcription factors is observed downstream of Akt. Mainly, this compartmentalization process is mandatory to induce T cell growth triggered by the T cell/antigen-presenting cell interaction. These findings demonstrate that to initiate cell cycle progression the formation of the immunological synapse is an undemanding tactic used by primary T cells to securely maintain the 3'-phosphoinositide-dependent mitotic switch governed by the spatial control of FoxO transcription factors.
Cell Proliferation↗
PI3-kinase and the control of T cell growth and proliferation by FoxOs.
Numerous cancers are caused by an uncontrolled uncontrolled activity of the PI3-kinase pathway. The proto-oncogene Akt, one of its main effectors, commands several molecular switches involved in cell survival and proliferation. One of these switches is represented by a group of related molecules belonging to the Forkhead family of transcription factors, called FoxOs. FoxOs negatively control cell cycle entry and this process emerges now as a mainstream mechanism used by various cell types to escape cell quiescence. In the light of recent works, FoxOs seem also to have a key role in the proliferative response of immune cells, especially in the clonal expansion of T lymphocytes induced by antigen. Experimental evidence supporting a relationship in T cells between PI3-kinase metabolism and these growth suppressive genes will be described in this mini-review.
Animals↗
Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control.
We have previously reported at the single cell level that PI3K is activated after conjugate formation between T lymphocytes and APCs. However, in contrast to cells exposed to an asymmetrical signal that usually increase 3'-phosphoinositides (3'-PI) transiently in the region of the activated receptors, T cells contacting APC accumulate 3'-PI across their whole plasma membrane far beyond the region of the immunological synapse (IS). Importantly, this effect is maintained over time, for hours, and although PI3K-dependent pathways translate in various cell types extracellular stimuli into a wide range of biological events, in primary T cells this stability is mostly required for cell division induced by Ag. Using imaging methodologies, the present article elucidates the molecular mechanisms responsible for this particular functioning of the PI3K pathway in primary human T lymphocytes interacting with APCs, especially with dendritic cells. The results reveal that the IS unremittingly recruits PI3K to maintain high 3'-PI levels in T cells through phosphotyrosine-dependent mechanisms, suggesting a major participation of class Ia PI3K. This persistent activation of PI3K results in the Akt-dependent sequestration of the FoxO transcription factor, FoxO1, outside the nucleus of T cells interacting with APCs. Using an active form of FoxO1, we demonstrate that this compartmentalization process can affect T cell growth after Ag recognition. We conclude that the need for sustained PI3K signaling within the consolidated IS is probably an undemanding tactic used by primary T cells critical for initiating cell cycle progression through the prolonged inactivation of FoxO1, one important factor that can control cell quiescence.
Active Transport, Cell Nucleus↗
DNAM-1 and PVR regulate monocyte migration through endothelial junctions.
DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity. We demonstrated recently that DNAM-1 triggers NK cell-mediated killing of tumor cells upon engagement by its two ligands, poliovirus receptor (PVR; CD155) and Nectin-2 (CD112). In the present paper, we show that PVR and Nectin-2 are expressed at cell junctions on primary vascular endothelial cells. Moreover, the specific binding of a soluble DNAM-1-Fc molecule was detected at endothelial junctions. This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by anti-Nectin-2 mAbs, which demonstrates that PVR is the major DNAM-1 ligand on endothelial cells. Because DNAM-1 is highly expressed on leukocytes, we investigated the role of the DNAM-1-PVR interaction during the monocyte transendothelial migration process. In vitro, both anti-DNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium. Moreover, after anti-DNAM-1 or anti-PVR mAb treatment, monocytes were arrested at the apical surface of the endothelium over intercellular junctions, which strongly suggests that the DNAM-1-PVR interaction occurs during the diapedesis step. Altogether, our results demonstrate that DNAM-1 regulates monocyte extravasation via its interaction with PVR expressed at endothelial junctions on normal cells.
Antigens, Differentiation, T-Lymphocyte↗